Times of Our Lives

B I O L O G Y

T I M E S

COPYRIGHT 2002 SCIENTIFIC AMERICAN, INC.

• In the brain, a “stopwatch”

can track seconds, minutes

and hours.

• Another timepiece in the

brain, more a clock than a

stopwatch, synchronizes

many bodily functions with

day and night. This same

clock may account for

seasonal affective disorder.

• A molecular hourglass that

governs the number of

times a cell can divide might

put a limit on longevity.

w w w . s c i a m . c o m S C I E N T I F I C A M E R I C A N 59

TOM

DR

APE

R D

ESI

GN

; N

ASA/

NSS

DC

(Ea

rth

an

dm

oon

); C

OR

BIS

(b

ase

ba

ll p

itch

era

nd

hor

n p

lay

er);

TO

MM

Y FL

YNN

Ph

oton

ica

(ala

rm c

lock

); C

OR

BIS

(b

rea

kfa

st);

JO

HN

TE

RR

EN

CE

TU

RN

ER

Get

ty I

ma

ges

(h

igh

wa

y);

R

OB

ER

T D

ALY

Ston

e (d

inn

er t

ab

le);

ER

ICA

McC

ON

NE

LL G

etty

Im

ag

es (

bru

shin

g t

eeth

);

GE

OFF

MAN

ASSE

Au

rora

(ch

ild

rea

din

g);

YO

SHIN

OR

I W

ATAB

E P

hot

onic

a (

nig

ht

sky

)

a fact of life that has been felt by all organismsin every era. For the morning glory that spreadsits petals at dawn, for geese flying south in au-tumn, for locusts swarming every 17 years andeven for lowly slime molds sporing in daily cy-cles, timing is everything. In human bodies, bio-logical clocks keep track of seconds, minutes,days, months and years. They govern the split-second moves of a tennis serve and account forthe trauma of jet lag, monthly surges of men-strual hormones and bouts of wintertime blues.Cellular chronometers may even decide whenyour time is up. Life ticks, then you die.

The pacemakers involved are as different asstopwatches and sundials. Some are accurate andinflexible, others less reliable but subject to con-scious control. Some are set by planetary cycles,others by molecular ones. They are essential tothe most sophisticated tasks the brain and bodyperform. And timing mechanisms offer insightsinto aging and disease. Cancer, Parkinson’s dis-ease, seasonal depression and attention-deficitdisorder have all been linked to defects in bio-logical clocks.

The physiology of these timepieces is notcompletely understood. But neurologists and oth-er clock researchers have begun to answer someof the most pressing questions raised by humanexperience in the fourth dimension. Why, for ex-ample, a watched pot never boils. Why time flieswhen you’re having fun. Why all-nighters cangive you indigestion, and why people live longerthan hamsters. It’s only a matter of time before

clock studies resolve even more profound quan-daries of temporal existence.

The Psychoactive StopwatchI F THIS ARTICLE intrigues you, the time youspend reading it will pass quickly. It’ll drag if youget bored. That’s a quirk of a “stopwatch” in thebrain—the so-called interval timer—that markstime spans of seconds to hours. The interval timerhelps you figure out how fast you have to run tocatch a baseball. It tells you when to clap to yourfavorite song. It lets you sense how long you canlounge in bed after the alarm goes off.

Interval timing enlists the higher cognitivepowers of the cerebral cortex, the brain centerthat governs perception, memory and consciousthought. When you approach a yellow trafficlight, for example, you time how long it has beenyellow and compare that with a memory of howlong yellow lights usually last. “Then you have tomake a judgment about whether to put on thebrakes or keep driving,” says Stephen M. Rao ofthe Medical College of Wisconsin.

Rao’s studies with functional magnetic reso-nance imaging (fMRI) have pointed to the partsof the brain engaged in each of those stages. In thefMRI machine, subjects listen to two pairs oftones and decide whether the interval between thesecond pair is shorter or longer than the intervalbetween the first. The brain structures that are in-volved in the task consume more oxygen thanthose that are not involved, and the fMRI scanrecords changes in blood flow and oxygenation

O V E R V I E W

OF OUR LIVESWhether they’re counting minutes, months or years,

biological clocks help to keep our brains and bodies running on schedule By Karen Wright

The late biopsychologist John Gibbon called time the “primordial context”:


once every 250 milliseconds. “Whenwe do this, the very first structures thatare activated are the basal ganglia,”Rao says.

Long associated with movement,this collection of brain regions has re-cently become a prime suspect in thesearch for the interval-timing mecha-nism as well. One area of the basal gan-glia, the striatum, hosts a population ofconspicuously well-connected nervecells that receive signals from otherparts of the brain. The long arms ofthese striatal cells are covered with be-tween 10,000 and 30,000 spines, eachof which gathers information from adifferent neuron in another locale. If thebrain acts like a network, then the stri-atal spiny neurons are critical nodes.“This is one of only a few places in thebrain where you see thousands of neu-

rons converge on a single neuron,” saysWarren H. Meck of Duke University.

Striatal spiny neurons are central toan interval-timing theory Meck devel-oped over the past decade with Gibbon,who worked at Columbia Universityuntil his death last year. The theoryposits a collection of neural oscillatorsin the cerebral cortex: nerves cells firingat different rates, without regard totheir neighbors’ tempos. In fact, manycortical cells are known to fire at ratesbetween 10 and 40 cycles per secondwithout external provocation. “Allthese neurons are oscillating on theirown schedules,” Meck says, “like peo-ple talking in a crowd. None of themare synchronized.”

The cortical oscillators connect tothe striatum via millions of signal-car-rying arms, so the striatal spiny neuronscan eavesdrop on all those haphazard“conversations.” Then something—ayellow traffic light, say—gets the corti-cal cells’ attention. The stimulationprompts all the neurons in the cortex tofire simultaneously, causing a charac-teristic spike in electrical output some

300 milliseconds later. This attentionalspike acts like a starting gun, afterwhich the cortical cells resume their dis-orderly oscillations.

But because they have begun simul-taneously, the cycles now make a dis-tinct, reproducible pattern of nerve ac-tivation from moment to moment. Thespiny neurons monitor those patterns,which help them to “count” elapsedtime. At the end of a specified interval—when, for example, the traffic lightturns red—a part of the basal gangliacalled the substantia nigra sends a burstof the neurotransmitter dopamine tothe striatum. The dopamine burst in-duces the spiny neurons to record thepattern of cortical oscillations they re-ceive at that instant, like a flashbulb ex-posing the interval’s cortical signatureon the spiny neurons’ film. “There’s a

unique time stamp for every intervalyou can imagine,” Meck says.

Once a spiny neuron has learnedthe time stamp of the interval for a giv-en event, subsequent occurrences of theevent prompt both the “firing” of thecortical starting gun and a burst of do-pamine at the beginning of the interval[see top illustration on opposite page].The dopamine burst now tells the spinyneurons to start tracking the patterns ofcortical impulses that follow. When thespiny neurons recognize the time stampmarking the end of the interval, theysend an electrical pulse from the stria-tum to another brain center called thethalamus. The thalamus, in turn, com-municates with the cortex, and thehigher cognitive functions—such asmemory and decision making—takeover. Hence, the timing mechanismloops from the cortex to the striatum tothe thalamus and back to the cortexagain.

If Meck is right and dopaminebursts play an important role in fram-ing a time interval, then diseases anddrugs that affect dopamine levels

should also disrupt that loop. So farthat is what Meck and others havefound. Patients with untreated Parkin-son’s disease, for example, release lessdopamine into the striatum, and theirclocks run slow. In trials these patientsconsistently underestimate the durationof time intervals. Marijuana also low-ers dopamine availability and slowstime. Recreational stimulants such ascocaine and methamphetamine in-crease the availability of dopamine andmake the interval clock speed up, sothat time seems to expand. Adrenalineand other stress hormones make theclock speed up, too, which may be whya second can feel like an hour duringunpleasant situations. States of deepconcentration or extreme emotion mayflood the system or bypass it altogeth-er; in such cases, time may seem to stand

still or not exist at all. Because an at-tentional spike initiates the timing pro-cess, Meck thinks people with atten-tion-deficit hyperactivity disorder mightalso have problems gauging the truelength of intervals.

The interval clock can also be trainedto greater precision. Musicians and ath-letes know that practice improves theirtiming; ordinary folk can rely on trickssuch as chronometric counting (“oneone-thousand”) to make up for themechanism’s deficits. Rao forbids hissubjects from counting in experimentsbecause it could activate brain centers re-lated to language as well as timing. Butcounting works, he says—well enough toexpose cheaters. “The effect is so dra-matic that we can tell whether they’recounting or timing based just on the ac-curacy of their responses.”

The Somatic SundialONE OF THE VIRTUES of the inter-val-timing stopwatch is its flexibility.You can start and stop it at will or ig-nore it altogether. It can work sublimi-nally or submit to conscious control.

60 S C I E N T I F I C A M E R I C A N S E P T E M B E R 2 0 0 2

“There’s a unique time stamp for every interval you can imagine.” —Warren H. Meck, Duke University


M E C H A N I S M S


TER

ESE

WIN

SLO

W

SCIENTISTS ARE UNCOVERING the workings of two neural timepieces: an interval timer (top), which measures intervals lasting up tohours, and a circadian clock (bottom), which causes certain body processes to peak and ebb on 24-hour cycles. —K.W.

Clocks in the Brain

The Circadian ClockDAILY CYCLES OF LIGHT AND DARK influence when manyphysiological processes that operate on 24-hourcycles will be most and least active. The brain tracksfluctuations in light with the help of ganglion calls inthe retina of the eye. A pigment in some of the cells—melanopsin—probablydetects light, leading the retinal ganglioncells to send information about itsbrightness and duration to thesuprachiasmatic nucleus (SCN) of thebrain. Then the SCN dispatches theinformation to the parts of the brain andbody that control circadian processes.Researchers best understand the eventsleading the pineal gland to secrete melatonin, sometimes calledthe sleep hormone (diagram). In response to daylight, the SCNemits signals (red arrow) that stop another brain region—theparaventricular nucleus—from producing a message that wouldultimately result in melatonin’s release. After dark, however, theSCN releases the brake, allowing the paraventricular nucleus torelay a “secrete melatonin” signal (green arrows) throughneurons in the upper spine and the neck to the pineal gland.

Signal emitted after SCNstops inhibiting its release

Melatonin

Paraventricularnucleus

AFTER BRAKE IS RELEASED

Suprachiasmaticnucleus

Blood-stream

Light

Retina

Ganglion cell

Optic nerve

Pineal gland

ab

c

d

Corticalneuron

Thalamus

TIME’S-UPSIGNAL

START SIGNAL

Striatum

Substantia nigra

TIME’S UP!

Spinyneuron

Pineal gland

The Interval TimerACCORDING TO ONE MODEL, the onset of anevent lasting a familiar amount of time (such as the switching on of a four-second yellowtraffic light) activates the “start button” of theinterval timer by evoking two brain responses.It induces a particular subset of cortical nervecells that fire at different rates (a) tomomentarily act together (b and green arrowson brain), and it prompts neurons of thesubstantia nigra to release a burst of thesignaling chemical dopamine (purple arrow).Both signals impinge on spiny cells of thestriatum (c), which proceed to monitor theoverall patterns of impulses coming from thecortical cells after those neurons resume theirvarious firing rates. Because the cortical cellsact in synchrony at the start of the interval, thesubsequent patterns occur in the samesequence every time and take a unique formwhen the end of the familiar interval is reached(d). At that point, the striatum sends a “time’sup” signal (red arrows) through other parts ofthe brain to the decision-making cortex.


But it won’t win any prizes for accura-cy. The precision of interval timers hasbeen found to range from 5 to 60 per-cent. They don’t work too well if you’redistracted or tense. And timing errorsget worse as an interval gets longer.“Hence the instruments we all wear onour wrists,” Rao notes.

Fortunately, a more rigorous time-piece chimes in at intervals of 24 hours.The circadian clock—from the Latincirca (“about”) and diem (“a day”)—

tunes our bodies to the cycles of sun-light and darkness caused by the earth’srotation. It helps to program the dailyhabit of sleeping at night and waking inthe morning. But its influence extendsmuch further. Body temperature regu-larly peaks in the late afternoon or ear-ly evening and bottoms out a few hoursbefore we rise in the morning. Blood

pressure typically starts to surge be-tween 6:00 and 7:00 A.M. Secretion ofthe stress hormone cortisol is 10 to 20times higher in the morning than atnight. Urination and bowel movementsare generally suppressed at night andpick up again in the morning.

The circadian timepiece is more likea clock than a stopwatch because it runswithout the need for a stimulus from theexternal environment. Studies of volun-teer cave dwellers and other humanguinea pigs have demonstrated that cir-cadian patterns persist even in the ab-sence of daylight, occupational demandsand caffeine. And they are expressed inevery cell of the body. Confined to apetri dish under constant lighting, hu-man cells still follow 24-hour cycles ofgene activity, hormone secretion and en-ergy production. The cycles are hard-wired, and they vary by as little as 1 per-cent: just minutes a day.

But if light isn’t required to establisha circadian cycle, it is needed to syn-chronize the phase of the hardwiredclock with natural day and night cycles.Like an ordinary clock that runs a few

minutes slow or fast each day, the cir-cadian clock needs to be continually re-set to stay accurate. Neurologists havemade great progress in understandinghow daylight sets the clock. Two clus-ters of 10,000 nerve cells in the hypo-thalamus of the brain have long beenconsidered the clock’s locus. Decades ofanimal studies have demonstrated thatthese centers, each called a suprachias-matic nucleus (SCN), drive daily fluctu-ations in blood pressure, body temper-ature, activity level and alertness. TheSCN also tells the brain’s pineal glandwhen to release melatonin, which pro-motes sleep in humans and is secretedonly at night.

Earlier this year separate teams ofresearchers proved that dedicated cellsin the retina of the eye transmit infor-mation about light levels to the SCN.

These cells—a subset of those known asganglion cells—operate completely in-dependently of the rods and cones thatmediate vision, and they are far less re-sponsive to sudden changes in light.That sluggishness befits a circadian sys-tem. It would be no good if watchingfireworks or going to a movie matineetripped the mechanism.

But the SCN’s role in circadianrhythms is being reevaluated in view ofother findings. Until recently, scientistsassumed that the SCN somehow coor-dinated all the individual cellular clocksin the body’s organs and tissues. Then,in the mid-1990s, researchers discov-ered four critical genes that govern cir-cadian cycles in flies, mice and humans.These genes turned up not just in theSCN but everywhere else, too. “Theseclock genes are expressed throughoutthe whole body, in every tissue,” saysJoseph Takahashi of Northwestern Uni-versity. “We didn’t expect that.”

And this year researchers at Har-vard University reported that the ex-pression of more than 1,000 genes in theheart and liver tissue of mice varied in

regular 24-hour periods. But the genesthat showed these circadian cycles dif-fered in the two tissues, and their ex-pression peaked in the heart at differenthours than in the liver. “They’re all overthe map,” says Michael Menaker of theUniversity of Virginia. “Some are peak-ing at night, some in the morning andsome in the daytime.”

Menaker has recently shown thatspecific feeding schedules can shift thephase of the liver’s circadian clock,overriding the light-dark rhythm fol-lowed by the SCN. When lab rats thatusually ate at will were fed just once aday, for example, peak expression of aclock gene in the liver shifted by 12hours, whereas the same clock gene inthe SCN stayed locked in sync withlight schedules. It makes sense that dai-ly rhythms in feeding would affect the

liver, given its role in digestion. Re-searchers think circadian clocks in oth-er organs and tissues may respond toother external cues—including stress,exercise, and temperature changes—

that occur regularly every 24 hours.No one is ready to dethrone the SCN:its authority over body temperature,blood pressure and other core rhythmsis still secure. But this brain center is nolonger thought to rule the peripheralclocks with an iron fist. “We have os-cillators in our organs that can func-tion independently of our oscillators inour brain,” Takahashi says.

The autonomy of the peripheralclocks makes a phenomenon such as jetlag far more comprehensible. Whereasthe interval timer, like a stopwatch, canbe reset in an instant, circadian rhythmstake days and sometimes weeks to ad-just to a sudden shift in day length ortime zone. A new schedule of light willslowly reset the SCN clock. But the oth-er clocks may not follow its lead. Thebody is not only lagging; it’s lagging ata dozen different paces.

Jet lag doesn’t last, presumably be-


A virtue of the interval-timing stopwatchis its flexibility. You can start and stop it at will.


cause all of those different drummerseventually sync up again. But shiftworkers, party animals, college stu-dents and other night owls face a worsechronodilemma. They may be leadinga kind of physiological double life.Even if they get plenty of shut-eye byday, their core rhythms are still ruled bythe SCN—hence, the core functionscontinue “sleeping” at night. “You canwill your sleep cycle earlier or later,”says Alfred J. Lewy of the OregonHealth & Science University. “But youcan’t will your melatonin levels earlieror later, or your cortisol levels, or yourbody temperature.”

Meanwhile their schedules for eat-ing and exercising could be settingtheir peripheral clocks to entirely dif-ferent phases from either the sleep-wake cycle or the light-dark cycle.With their bodies living in so manytime zones at once, it’s no wonder shift

workers have an increased incidence ofheart disease, gastrointestinal com-plaints and, of course, sleep disorders.

A Clock for All SeasonsJET LAG AND SHIFT WORK are ex-ceptional conditions in which the in-nate circadian clock is abruptly thrownout of phase with the light-dark cyclesor sleep-wake cycles. But the samething can happen every year, albeit lessabruptly, when the seasons change. Re-search shows that although bedtimesmay vary, people tend to get up atabout the same time in the morningyear-round—usually because their dogs,kids, parents or careers demand it. Inthe winter, at northern latitudes, thatmeans many people wake up two tothree hours before dawn. Their sleep-wake cycle is several time zones awayfrom the cues they get from daylight.

The mismatch between day length

and daily life could explain the syn-drome known as seasonal affective dis-order, or SAD. In the U.S., SAD afflictsas many as one in 20 adults with de-pressive symptoms such as weight gain,apathy and fatigue between Octoberand March. The condition is 10 timesmore common in the north than thesouth. Although SAD occurs seasonal-ly, some experts suspect it is actually acircadian problem. Lewy’s work sug-gests that SAD patients would come outof their depression if they could get upat the natural dawn in the winter. In hisview, SAD is not so much a pathologyas evidence of an adaptive, seasonalrhythm in sleep-wake cycles. “If we ad-justed our daily schedules according tothe seasons, we might not have season-al depression,” Lewy says. “We got intotrouble when we stopped going to bedat dusk and getting up at dawn.”

If modern civilization doesn’t honor


TER

ESE

WIN

SLO

W

The Rhythm of LifeTHE CIRCADIAN CLOCKaffects the dailyrhythms of manyphysiologicalprocesses. The diagram at the rightdepicts the circadianpatterns typical ofsomeone who risesearly in the morning,eats lunch around noon and sleeps atnight. Althoughcircadian rhythms tend to besynchronized withcycles of light and dark, other factors—

such as ambienttemperature, mealtimes, stress andexercise—can influence the timing as well. —K.W.

C Y C L I C E V E N T S

2:00 A.M.Deepest sleep

4:30 A.M.Lowest bodytemperature

6:45 A.M.Sharpest blood pressure rise

6:00 A.M.6:00 P.M.

7:30 A.M.Melatonin

secretion stops

10:00 A.M.High alertness

2:30 P.M.Best coordination

3:30 P.M.Fastest reaction time

5:00 P.M.Greatest cardiovascular

efficiency and muscle strength

6:30 P.M.Highest blood pressure

7:00 P.M.Highest body temperature

9:00 P.M.Melatonin secretion starts

S O U R C E : T h e B o d y C l o c k G u i d e t o B e t t e r H e a l t h , b y M i c h a e l S m o l e n s k y a n d L y n n e L a m b e r g , H e n r y H o l t , 2 0 0 0

12:00MIDNIGHT

12:00NOON

8:30 A.M.Bowel movement

likely

10:30 P.M.Bowel

movementssuppressed


seasonal rhythms, it’s partly because hu-man beings are among the least season-ally sensitive creatures around. SAD isnothing compared to the annual cyclesother animals go through: hibernation,migration, molting and especially mat-ing, the master metronome to which allother seasonal cycles keep time. It is pos-sible that these seasonal cycles may alsobe regulated by the circadian clock,which is equipped to keep track of thelength of days and nights. Darkness, asdetected by the SCN and the pinealgland, prolongs melatonin signals in thelong nights of winter and reduces themin the summer. “Hamsters can tell thedifference between a 12-hour day, whentheir gonads don’t grow, and a 12-hour-15-minute day, when their gonads dogrow,” Menaker says.

If seasonal rhythms are so robust inother animals, and if humans have the

equipment to express them, then howdid we ever lose them? “What makesyou think we ever had them?” Menakerasks. “We evolved in the tropics.” Men-aker’s point is that many tropical ani-mals don’t exhibit dramatic patterns ofannual behavior. They don’t need them,because the seasons themselves vary solittle. Most tropical animals mate with-out regard to seasons because there is no“best time” to give birth. People, too,are always in heat. As our ancestorsgained greater control of their environ-ment over the millennia, seasons prob-ably became an even less significant evo-lutionary force.

But one aspect of human fertility iscyclical: women and other female pri-mates produce eggs just once a month.The clock that regulates ovulation andmenstruation is a well-documentedchemical feedback loop that can be ma-

nipulated by hormone treatments, exer-cise and even the presence of other men-struating women. But the reason for thespecific duration of the menstrual cycleis unknown. The fact that it is the samelength as the lunar cycle is a coincidencefew scientists have bothered to investi-gate, let alone explain. No convincinglink has yet been found between themoon’s radiant or gravitational energyand a woman’s reproductive hormones.In that regard, the monthly menstrualclock remains a mystery—outdone per-haps only by the ultimate conundrum,mortality.

Time the AvengerPEOPLE TEND TO EQUATE agingwith the diseases of aging—cancer,heart disease, osteoporosis, arthritisand Alzheimer’s, to name a few—as ifthe absence of disease would be enoughto confer immortality. Biology suggestsotherwise.

Modern humans in developed coun-tries have a life expectancy of more than70 years. The life expectancy of youraverage mayfly, in contrast, is a day. Bi-ologists are just beginning to explorewhy different species have different lifeexpectancies. If your days are num-bered, what’s doing the counting?

At a recent meeting hosted by theNational Institute on Aging, partici-pants challenged many common as-sumptions about the factors that deter-mine natural life span. The answer can-not lie solely with a species’ genetics:worker honeybees, for example, last afew months, whereas queen bees live foryears. But genetics are important: a sin-gle-gene mutation in mice can producea strain that lives up to 50 percentlonger than usual. High metabolic ratescan shorten life span, yet many speciesof birds, which have fast metabolisms,live longer than mammals of compara-ble body size. And big, slow-metaboliz-ing animals do not necessarily outlastthe small ones. The life expectancy of aparrot is about the same as a human’s.Among dog species, small breeds typi-cally live longer than large ones.

Scientists in search of the limits tohuman life span have traditionally ap-


TOM

DR

APE

R D

ESI

GN

; FR

ANS

LAN

TIN

G M

ind

en P

ictu

res

(sw

an

s a

nd

bu

tter

flie

s);

GE

OR

GE

MC

CAR

THY

Cor

bis

(m

ouse

); M

ARK

JO

NE

S M

ind

en P

ictu

res

(pen

gu

in);

NAJ

LAH

FE

ANN

Y SA

BA

(lig

ht

ther

ap

y)

Turn, TurnMOST ANIMALS experiencedramatic seasonal cycles: theymigrate, hibernate, mate andmolt at specific times of the year(top four photographs). Thetesticles of hamsters, forexample, quadruple in size asmating season approaches.These cycles are hardwired:captive ground squirrels continueto hibernate seasonally even whenkept in constant temperatureswith unvarying periods of light and dark. Likewise, birds in stable laboratory conditions get restless at migration time andkeep molting and fattening inyearly cycles.

The only vestige of seasonality in humans may be seasonalaffective disorder, a yearly boutof depression that strikes someindividuals in winter and can beremedied with light therapy(bottom photograph)—or merelyby sleeping until the sun comes up. —K.W.

S E A S O N A L C L O C K S


proached the subject from the cellularlevel rather than considering whole or-ganisms. So far the closest thing theyhave to a terminal timepiece is the so-called mitotic clock. The clock keepstrack of cell division, or mitosis, theprocess by which a single cell splits intotwo. The mitotic clock is like an hour-glass in which each grain of sand rep-resents one episode of cell division. Justas there is a finite number of grains inan hourglass, there seems to be a ceilingon how many times normal cells of thehuman body can divide. In culture theywill undergo 60 to 100 mitotic divi-sions, then call it quits. “All of a suddenthey just stop growing,” says John Se-divy of Brown University. “They re-spire, they metabolize, they move, butthey will never divide again.”

Cultured cells usually reach this state

of senescence in a few months. Fortu-nately, most cells in the body dividemuch, much more slowly than culturedcells. But eventually—perhaps after 70years or so—they, too, can get put out topasture. “What the cells are counting isnot chronological time,” Sedivy says.“It’s the number of cell divisions.”

In 1997 Sedivy reported that hecould squeeze 20 to 30 more cycles outof human fibroblasts by mutating a sin-gle gene. This gene encodes a proteincalled p21, which responds to changesin structures called telomeres that capthe end of chromosomes. Telomeres aremade of the same stuff that genes are:DNA. They consist of thousands ofrepetitions of a six-base DNA sequencethat does not code for any known pro-tein. Each time a cell divides, chunks ofits telomeres are lost. Young humanembryos have telomeres between 18,000and 20,000 bases long. By the timesenescence kicks in, the telomeres areonly 6,000 to 8,000 bases long.

Biologists suspect that cells becomesenescent when telomeres shrink belowsome specific length. Recently Titia de

Lange of the Rockefeller Universityproposed a new explanation for thislink. In healthy cells, she showed, thechromosome ends are looped back onthemselves like a hand tucked in apocket. The “hand” is the last 100 to200 bases of the telomere, which aresingle-stranded, not paired like the rest.With the help of more than a dozen spe-cialized proteins, the single-strandedend is inserted into the double strandsupstream for protection.

If telomeres are allowed to shrinkenough, “they can no longer do thislooping trick,” de Lange says. Untucked,a single-stranded telomere end is vul-nerable to fusion with other single-stranded ends. The fusion wreaks hav-oc in a cell by stringing together all thechromosomes. That could be why Se-divy’s mutated p21 cells died after they

got in their extra rounds of mitosis.Other cells bred to ignore short telo-meres have turned cancerous. The jobof normal p21 and telomeres them-selves may be to stop cells from divid-ing so much that they die or becomemalignant. Cellular senescence couldactually be prolonging human life,rather than spelling its doom. It mightbe cells’ imperfect defense against ma-lignant growth and certain death.

“Our hope is that we’ll gain enoughinformation from this reductionist ap-proach to help us understand what’s go-ing on in the whole person,” de Langecomments.

For now, the link between short-ened telomeres and aging is tenuous atbest. Most cells do not need to keep di-

viding to do their job—white blood cellsthat fight infection and sperm precur-sors being obvious exceptions. Butmany older people do die of simple in-fections that a younger body couldwithstand. “Senescence probably hasnothing to do with the nervous sys-tem,” Sedivy says, because most nervecells do not divide. “On the other hand,it might very well have something to dowith the aging of the immune system.”

In any case, telomere loss is just oneof the numerous insults cells sustainwhen they divide, says Judith Campisiof Lawrence Berkeley National Labo-ratory. DNA often gets damaged whenit is replicated during cell division, socells that have split many times aremore likely to harbor genetic errorsthan young cells. Genes related to agingin animals and people often code for

proteins that prevent or repair thosemistakes. And with each mitotic epi-sode, the by-products of copying DNAbuild up in cell nuclei, complicatingsubsequent bouts of replication.

“Cell division is very risky busi-ness,” Campisi observes. So perhaps itis not surprising that the body puts a capon mitosis. And cheating cell senescenceprobably wouldn’t grant immortality.Once the grains of sand have fallenthrough the mitotic hourglass, there’sno point in turning it over again.

Karen Wright is a science writerbased in New Hampshire. Her workis featured in The Best AmericanScience and Nature Writing 2002(Mariner Books).


The Body Clock Guide to Better Health. Michael Smolensky and Lynne Lamberg. Henry Holt and Company, 2000.

Neuropsychological Mechanisms of Interval Timing Behavior. Matthew S. Matell and Warren H. Meck in BioEssays, Vol. 22, No. 1, pages 94–103; January 2000.

The Evolution of Brain Activation during Temporal Processing. Stephen M. Rao, Andrew R. Mayer and Deborah L. Harrington in Nature Neuroscience, Vol. 4, No. 3, pages 317–323; March 2001.

The Living Clock. John D. Palmer. Oxford University Press, 2002.

M O R E T O E X P L O R E

It is possible that seasonal cycles in animals may be regulated by the circadian clock.


Documents

Times of Our Lives